Ecosystems and Human Health - Chapter 6 pps

In 1810, a remarkable case of mass poisoning with mercury occurred.. Within 3 weeks, 200 men were affected with signs of mercury poisoning, including profuse salivation, weakness, tremor

chapter six Toxicity of metals

“Mad as a Hatter”

Introduction

The process of felting, employed in making hats many years ago, required the use of mercurial compounds and many hatters suffered from the CNS disturbances (including behavioral disorders) associated with mercury tox-icity Metal intoxication as an occupational disease may be 4000 years old Lead was produced as a by-product of silver mining as long ago as 2000 B.C Hippocrates described abdominal colic in a man who worked as a metal smelter in 370 B.C., and arsenic and mercury were known to the ancients even if their toxicity was not In 1810, a remarkable case of mass poisoning with mercury occurred The 74-gun man-o’-war HMS Triumph salvaged

130 tons of mercury from a Spanish vessel wrecked while returning from South America, where the mercury had been mined The mercury was con-tained in leather pouches, which became damp and rotten, allowing it to escape and vaporize Within 3 weeks, 200 men were affected with signs of mercury poisoning, including profuse salivation, weakness, tremor, partial paralysis, ulcerations of the mouth, and diarrhea Almost all animals on-board died, including mice, cats, a dog, and a canary Five men died When the vessel put in at Gibraltar for cleaning, all those working in the hold salivated profusely

The common nineteenth-century practice of adulterating foods and bev-erages (wine, beer, etc.) to increase profit led Accum to publish a treatise on the subject in 1820 Lead, copper, and mercury were frequently detected Methods were not yet in place to detect arsenic, which was found to be a widespread adulterant later in the century In 1875, the British Parliament passed the first Food and Drugs Act as a result of these investigations

In the past it was common to refer to heavy metal toxicity, as it was those metals that first emerged as industrial hazards Heavy metals are arbitrarily defined as those having double-digit specific gravities and they include platinum (21.45), plutonium (19.84), tungsten (19.3), gold (18.88), mercury (13.55), lead (11.35), and molybdenum (10.22) These are in contrast

to iron (7.87), manganese (7.21), chromium (7.18), zinc (7.13), selenium (4.78), and aluminum (2.70) Intermediate are copper (8.96) and cadmium (8.65)

In general, it can be seen that metals with specific gravities less than 8 are mostly essential trace nutritional elements (copper also is one and there-fore the exception, as is aluminum, which is not a nutritional element), whereas those having specific gravities greater than 8 are the more toxic ones It must be stressed once again that dose is all-important Aluminum, with a specific gravity of 2.70, has toxic properties Arsenic exists in two solid forms: yellow arsenic (1.97) and grey or metallic arsenic (5.73) Both are highly toxic

Lead (Pb)

The Latin word for lead is plumbum, hence the chemical designation Pb This word also gave origin to such English ones as plumb bob (a mason’s line with a metal ball attached for establishing vertical trueness), plummet (to fall as if leaden), and aplomb (to be as calm and undeviating as a plumb line) Lead was obviously well known to the ancients In fact, they spent a lot of time trying to turn it into gold (alchemy) Lead toxicity was also familiar to them Diascorides described its CNS toxicity as delirium Despite early knowledge of lead’s toxic effects, the low melting point of the metal, coupled with its density, made it popular and useful Well into the 1940s and early 1950s, it was possible to buy lead toys, and kits were available to cast lead soldiers and lead fishing weights An 1885 description

of chronic lead poisoning is as good as any to be found in a modern text:

The chief signs of chronic poisoning are those of general ill health; the digestion is disturbed, the appetite lessened, the bowels obstinately confined, the skin assumes a pecu-liar yellowish hue, and sometimes the sufferer is jaun-diced The gums show a black line from two to three lines

in breadth, which microscopical examination and chemical tests alike show to be composed of sulfide of lead; occa-sionally the teeth turn black The pulse is slow and all secretions are diminished Pregnant women have a ten-dency to abort There are also special symptoms, one of the most prominent of which is lead colic This colic is paroxysmal and excruciating.

Modern-day sources of lead are numerous In the eighteenth century, the industrial West discovered what the Chinese had known for centuries, namely that lead glazes produce crockery with a richer, smoother look From this source and from lead solder in cans and kettles and water pipes leached

by soft (but not hard) water, we consume about 150 µg/day In some areas, the figure may reach 1 to 2 mg Children are more vulnerable because all dirt and dust contain lead, especially in cities where lead from auto exhaust

(tetraethyl lead) settles out on the ground This will persist long after the conversion to lead-free auto fuel Children may also consume old lead-based paint, common in older buildings and which may also be on cheap wooden toys In children, CNS toxicity is the dominant feature This starts with vertigo and irritability, progressing to delirium, vomiting, and convulsions The mortality rate is about 25% if treated and about 65% if untreated In infants, exposure produces progressive mental deterioration after 18 months, with loss of motor skills, retarded speech development, and hyperkinesis in some cases In the United States, the Lead Paint Poison Prevention Program was introduced in 1970 Since that time, the mean blood lead level of U.S children has fallen from over 1 µmol/L (20.7 µg/dL) to less than 0.25 µmol/L (5.2 µg/dL) Only two deaths in children from acute lead encephalopathy have been reported in the past 20 years

Children are not the only victims of lead poisoning from lead paint Sandblasting of old, lead-painted buildings may, over time, cause chronic lead poisoning in workers who inhale the dust Proper respirators and pro-tective clothing are required for sandblasters Heating of lead paint to a sufficiently high temperature can release lead fumes that can be inhaled Cutting torches can produce sufficient heat to do this

In all exposed individuals, subchronic toxicity can involve interference with mitochondrial heme synthesis at several levels, with resultant hypo-chromic (pale) microcytic (small) anemia The pathway involved in this is illustrated in Figure 25

Toxicokinetics of lead

Elemental lead is not absorbed by the skin or through the alveoli of the lungs Inhaled particulate lead is returned to the pharynx by the bronchial cilia and swallowed Tetraethyl lead, however, may be absorbed across the skin and alveoli and readily penetrates CNS Most of it is destroyed in exhaust emis-sions but sniffing leaded gasoline can result in severe CNS damage Gastrointestinal absorption of lead probably occurs via calcium channels

as lead is a divalent cation (Pb2+) It first appears in red blood cells, then hepatocytes, and then the epithelial cells of the renal tubules It is gradually redistributed to hair, teeth, and bones where 95% of it is stored harmlessly The t1/2 in blood is about 30 days; in bone, 25 years Little reaches the adult brain but much more enters the infant brain Renal excretion is the main route of elimination

Cellular toxicity of lead

Lead affects oxidative phosphorylation and ATP synthesis in the mitochon-drion It also increases red cell fragility and inhibits sodium/potassium ATPase Kidney tubular cells become necrotic and chronic exposure may lead to interstitial nephritis Nuclear inclusion bodies, consisting of lead bound to a protein, may be formed in renal cells This may be considered

as a protective mechanism Carcinogenesis has been demonstrated in exper-imental animals and chromosomal abnormalities have been observed, but evidence of tumor production in humans is scarce Most of the toxic effects

of lead and other heavy metals can be explained by their affinity for thiol groups This is also the basis of chelation therapy

Fetal toxicity

A characteristic of all metals is their ability to penetrate the placental barrier,

so that fetal toxicity can occur as a result of maternal exposure Lead (Pb) is considered to be a human carcinogen and pregnant women are generally removed from jobs where exposure may occur

Prolonged exposure to low levels of Pb leads to impairment of the learning process Current experimental evidence suggests that Pb is inhibi-tory to the NMDA receptor complex Reduced availability of dopamine also could be involved and hypocholinergic function has been described

Figure 25 A simplified scheme showing points of interference of lead in heme syn-thesis See also Figure 22 for ALA synthase and heme inhibition.

SUCCINYL CoA + GLYCINE GAMMA AMINOLEVULINIC ACID

COPROPORPHYRINOGEN UROPORPHYRINOGEN PORPHYROBILINOGEN

ALA-DEHYDRATASE

COPROPORPHYRINOGEN -OXIDASE

FERROCHELATASE

PROTOPORPHYRIN IX

CYTOCHROME-C mitochondrion

mitochondrion

mitochondrial wall cytosol

HEME HEME OXIDASE BILIRUBIN+Fe

ALA SYNTHASE

∗ Pb

∗ Pb

Pb ∗

Pb ∗

∗ Pb

+ 4 Fe

+ Fe

Pb chelators are the treatment of choice These bind Pb (and other divalent cations) so that it can be excreted Calcium/sodium ethylenediaminetetraac-etate (CaNa2EDTA) and dimercaprol (British antilewisite, BAL) are given intramuscularly followed by oral penicillamine for several weeks BAL was developed during World War II as a treatment for lewisite, a vesicant arseni-cal poison gas A newer chelator is meso-2,3,-dimercaptosuccinic acid (DMSA) The chemical structures of these chelators are shown in Figure 26

In the case of EDTA, Pb is exchanged for Ca2+, whereas with the others, the

Pb is bound to sulfhydryl groups The complexes are excreted, primarily in urine A disadvantage of chelation therapy is that it does not remove Pb from the brain very efficiently

Despite 50 years of use, objective evidence for the benefit of chelation therapy for Pb poisoning is scanty It is widely agreed that it has drastically reduced the mortality from Pb encephalopathy if diagnosis and treatment are started early It also relieves Pb colic, malaise, basophilic stippling, and

it rapidly restores red-cell ALA dehydratase It does not influence the resid-ual manifestations of chronic Pb poisoning such as peripheral neuropathy

Mercury (Hg)

Mercury (Hg) exists in three forms: elemental mercury, inorganic compounds, and organic compounds Elemental mercury causes toxicity when the mer-cury vapor is inhaled, as exemplified by the episode described at the begin-ning of this chapter The major source of elemental mercury in the environ-ment is the natural degassing of the Earth’s crust Estimates of the level of mercury reaching the atmosphere range from 25,000 to 150,000 tons/yr, and

Figure 26 Chemical structures of some metal chelators.

D-PENICILLAMINE

H

H3C

CH3

H2

C

H

S

H

S

CH

CH2

O-O -O

O

O C

N Ca N

C

O O O

CH2 CH2

CH2 CH2 CH2

Na 2 /Ca EDTA

meso-DMSA

the atmosphere represents a major mechanism for global transport of metallic mercury Conversely, anthropogenic sources account for only 10,000 tons/yr; but because industrial effluent tends to be concentrated, these are the sources usually associated with toxicity Metallic mercury and its vapor can be an industrial hazard Mercury is used in the manufacture of chlorine and sodium hydroxide by the mercury cell process, in paint preservatives, and in the electronics industry It is a by-product of smelting processes (most mineral ores contain mercury), and it is released during fossil fuel combustion

Elemental mercury toxicity

In vapor form, elemental mercury is well absorbed across both the alveoli

of the lungs and the blood-brain barrier Acute poisoning usually occurs within several hours Weakness, chills, metallic taste, salivation, nausea, vomiting, diarrhea, labored breathing, cough, and tightness in the chest may ensue If the exposure is more prolonged, interstitial pneumonitis may develop Recovery is usually complete except that residual loss of pulmonary function may persist Chronic exposure to mercury vapor results in CNS disturbances, including tremor and a variety of behavioral changes that can include depression, irritability, shyness, instability, confusion, and forgetful-ness Mercury vapor from mercury nitrate formerly used in the felting pro-cess accounted for the “mad hatter” syndrome The behavioral abnormalities

of the “Mad Hatter” in Lewis Carroll’s The Adventures of Alice in Wonderland

were really quite mild, compared with the other characters, which is in keeping with the topsy-turvy world that Carroll created Thyroid distur-bances may also be present

Inorganic mercurial salts

Inorganic salts such as mercuric chloride can cause severe, acute toxicity The proteins of mucous membranes are precipitated, giving them an ash-gray color in the mouth and pharynx Intense abdominal pain and vomiting are common Loss of blood and fluid from the gastrointestinal tract results from sloughing of the mucosa in the stool and may lead to hypovolemia and shock Renal tubular necrosis occurs after acute exposure and glomerular damage is more common after chronic exposure A phenomenon called

“pink disease” or acrodynia commonly follows chronic exposure to mercury ions It is a flushing of the skin that is believed to have an allergic basis

Organic mercurials

Methylmercury is the most common cause of organic mercurial poisoning and the most important one environmentally It is extremely well absorbed from the gastrointestinal tract (90%) and deposited in the brain Because of its high affinity for SH groups, methylmercury binds to cysteine and this may then substitute for methionine and be incorporated into proteins This

can result in the formation of abnormal microtubles required for cell division and neuronal migration The main signs and symptoms are neurological and consist of visual disturbances, weakness, incoordination, loss of sensation, loss of hearing, joint pain, mental deterioration, tremor, and in severe cases, paralysis and death Infants exposed in utero may be deformed and retarded Experimentally, methylmercury has been shown in cell cultures to mobilize

Ca2+ from intracellular stores that are sensitive to inositol 1,4,5-trisphosphate Mercury is a waste product of many industrial processes It is methylated

in sediment by bacteria and cyanocobalamin Several outbreaks of methyl-mercury poisoning have occurred The most widely known began in 1953

in Minimata, Japan, near a plant that manufactured acetaldehyde and dis-charged mercury-containing compounds into Minimata Bay People who ate mollusks and large fish from the bay developed the symptoms that came to

be known as Minimata disease; 900 cases developed and there were 90 fatalities Because of the high fetal toxicity of mercury, many deformed infants were born Another source of mercury toxicity is the consumption

of seed grains treated with methylmercuric chloride as a fungicide Several mass poisonings have occurred around the world In Iraq in 1972, one such episode resulted in over 6500 cases of poisoning and 500 deaths

Mechanism of mercury toxicity

Mercury toxicity can be explained entirely by its ability to bind with the hydrogen of sulfhydryl (SH) groups to form mercaptides (i.e., X-Hg-SR and HgSR2, where X = an electronegative radical and R = a protein) Organic mercurials such as methylmercury form mercaptides, R-Hg-SR’ The term

mercapto means “to capture mercury” and refers to sulfur-containing groups Because SH groups are important components of many enzymes, mercury acts as an enzyme poison and interferes with cell function at many levels Mercury can also combine with other physiologically important ligands such

as phosphoryl, carboxyl, amide, and amine groups Metallic Hg vapor may

be oxidized by catalase enzyme in red blood cells to the less toxic divalent form Alcohol competitively inhibits this process Mercury was an important pharmaceutical agent for centuries, and its pharmacological properties also depend on its affinity for SH groups It was used as an antibacterial agent (for syphilis), as a laxative, in skin creams, and in diuretics Mercurial diuret-ics were still in use in the 1960s They were eventually replaced by safer agents Aminomercuric chloride may still appear in freckle-removing creams, and daily application for years may result in increases in 24-hr urine mercury excretions from 10 µg to 1 mg and the development of symptoms such as excessive salivation and insomnia

Treatment of mercury poisoning

Chelation therapy is recommended for elemental, inorganic mercury poi-soning Dimercaprol and penicillamine are SH-containing chelators Dimer-caprol is given intramuscularly and penicillamine, orally Hemodialysis can

also be used, and vomiting may be induced if there has been recent ingestion

of mercury These treatments are of little use in methylmercury poisoning, however Dimercaprol actually increases brain levels of methylmercury, and penicillamine and hemodialysis do not relieve symptoms Some success has been achieved with binding resins taken orally Because there is a significant enterohepatic recirculation of methylmercury (i.e., it is excreted in the bile and reabsorbed from the intestinal tract), binding it to a polythiol resin prevents its reabsorption because it is excreted in the feces

The Grassy Narrows story

In 1969, Norvald Fimreite, a Ph.D candidate in the Department of Zoology

at the University of Western Ontario, first made public his findings on the mercury contamination of fish in Canadian and border lakes The highest levels were recorded from a small lake, Pinchi, in British Columbia (10 ppm) and from Lake St Clair (7.03 ppm) in the Great Lakes waterway The (Cana-dian) federal standard for export and consumption was 0.5 ppm His report was a bombshell, coming on the heels of reports of Minamata disease from Japan Fimreite estimated that Canadian industry was releasing 200,000 lb of mercury annually into the environment Most of it came from chloralkali plants and from pulp and paper mills that used mercurials as antisliming (antialgal) agents and chlorine and alkali as bleaching agents The question

of mercury discharge from the Dow (Canada) Chemical plant had been raised

6 years earlier in the Ontario provincial legislature but nothing had been done

In 1970, the Ontario Water Resources Commission took steps to reduce Dow’s output; but in Dryden, near the Manitoba border, the Dryden Pulp and Paper Co (owned by the British Reed Group) had been emitting mercury vapor since 1962, and some workers developed bleeding gums and muscle twitches By 1970, it had pumped an estimated 20,000 lb of mercury into the surrounding environment, including discharges described as a brown froth into the Wabigoon River Raw sewage was also discharged into the Wabigoon River, providing a rich source of anaerobic bacteria to methylate elemental mercury The Wabigoon River is part of the English River system, and about

50 km downstream lie the Grassy Narrows and White Dog Indian reserves The residents gleaned a slim but adequate living as fishing guides and lived largely off the land, eating fish, deer, and moose supplemented with garden vegetables In March 1970, contamination of fish in Lake Erie was detected and the Lake St Clair and Lake Erie fisheries were closed Chloralkali plants and pulp mills were ordered to stop using mercury by the end of May after

a concerted attack in the Ontario legislature by opposition parties Mercury, however, is not biodegradable, and it is only when it is buried by uncon-taminated sediment that it ceases to be a threat

In June 1970, the Lamms, owners of Ball Lake Fishing Lodge, hired Fim-reite to conduct a survey of mercury levels in the fish of the English-Wabigoon system The findings were appalling Levels ranged from 13 to 30 ppm, as high as those from Minamata Bay The government lifted Fimreite’s license

to collect specimens for scientific purposes and ignored his appeals to test the residents of the reserves until his data were made public, when it conceded that it had similar findings A ban was placed on eating fish from the con-taminated area but otherwise the government continued to downplay the problem Tourist fishing dried up and the Indians went on welfare Blood levels of mercury were not seriously studied until 1973, and ranged from 45

to 289 ppb (normal is about 20 ppb for a city dweller) Some residents were showing signs of mercury poisoning and the incidence of stillbirths was rising The social costs of this tragedy were perhaps even greater than the direct effects of mercury In the years surrounding the discovery of mercury in the Grassy Narrows area, the death rate rose to 1 in 50, three times the national average Most were alcohol related Many of the deaths were newborn or very young infants Violence became rampant Dr Peter Newbury, also a graduate of the University of Western Ontario, conducted a study for the Society of Friends (Quaker) and the National Indian Brotherhood and felt that the CNS effects of mercury were a contributing factor in the violence Gasoline sniffing became common among young people (it remains a prob-lem on many reserves) The Grand Council of Treaty Three District, which includes Grassy Narrows and Kenora, completed a study in 1973 They found that in the preceding 42-month period, there had been 189 violent deaths of native people They reported 38 from gunshot, stabbing, or hang-ing, 30 in fires, 42 drownings, 25 from exposure, and 16 from car accidents

In the same year, members of the Ojibwa Warrior Society occupied Anicinabe Park on the outskirts of Kenora Barricades were erected and manned by armed warriors The park was claimed as Indian land The standoff lasted for several weeks but achieved little

Cadmium (Cd)

Cadmium is present naturally in the environment in very low levels, being solubilized during the weathering of rock (levels are about 0.03 µg/g of soil, 0.07 µg/mL of fresh water, and 1 ng/m3 of air) Dissolved cadmium may form a number of soluble and insoluble organic and inorganic compounds Cadmium is chemically similar to zinc and it is present in zinc ore in a ratio

of about 1/250 Most cadmium is produced as a by-product of electrolytic zinc plants It is used in metal plating, in the manufacture of nickel-cadmium batteries, in the manufacture of pigments, in plastic stabilizers, and, in small amounts, in photographic chemicals, catalysts, and fungicides used on golf courses Environmentally significant emissions come primarily from smelt-ing operations for copper, lead, and zinc, from auto exhaust, and from the manufacture of pigments and alloys (most nickel-cadmium batteries are imported into Canada) Cadmium is readily taken up by plants and stored

in the leaves and seeds It is present in sewage sludge fertilizers (recom-mended maximum, 20 ppm) Water pollution with cadmium may result in high levels in fish and especially in mollusks The main sources in the human

diet are organ meats (cadmium accumulates in liver and kidney), cereal grains, shellfish, and crustaceans

Cadmium toxicokinetics

Cadmium intake in Canada averages 50 to 100 µg/day from inhaled and ingested sources Inhaled, unpolluted air may contribute up to 0.15 µg/day, whereas breathing air near a smelter can raise the level to 10 µg/day Cigarettes contain cadmium and smoking increases exposure still further About 50% of inhaled cadmium is absorbed Only about 6% of ingested cadmium is absorbed, but it contributes most of the daily load The FAO/WHO recommends a maximum weekly intake of 500 µg Absorbed cadmium is bound to plasma albumin and cleared rapidly from the plasma

It is found in red cells only after high exposures It is rapidly distributed to the liver, pancreas, prostate, and kidney, with slow redistribution to the kidney until, over time, it contains most of the cadmium Renal levels increase up to age 50 and depend on the cumulative exposure The t1/2 in humans is about 20 years Cadmium is trapped in the kidney and liver by

a cysteine (i.e., SH)-rich protein called metallothionein with a high affinity for cadmium and zinc Cadmium normally binds to matallothionein, the synthesis of which is induced by the presence of the cadmium High doses, however, exceed the binding capacity of the protein, and the cadmium is free to bind to other essential cell components such as the basement mem-brane of the renal glomerulus

Cadmium toxicity

The kidney is the major organ of toxicity About 200 µg/g wet weight of kidney appears to be the critical concentration in the renal cortex for damage

to occur in the form of proximal tubule dysfunction Once renal disease develops, cadmium is lost from the kidney Nutritional deficiencies of zinc, iron, and calcium may predispose cadmium toxicity by increasing absorption from the gastrointestinal tract Calcium deficiency increases the synthesis of calcium-binding proteins and cadmium absorption Workers in metal refin-eries may be exposed to high levels of cadmium fumes and develop respi-ratory difficulties Chronic exposure may lead to obstructive pulmonary disease and emphysema A major exposure occurred in Japan in the late 1940s Effluent from a lead processing plant washed into adjacent rice pad-dies over decades, and the rice accumulated high levels of cadmium Because the people were calcium-deficient due to a poor diet, they developed acute cadmium toxicity with severe muscle pain, malabsorption, anemia, and renal failure The outbreak was named “Itai-Itai” (ouch-ouch) disease The fetus appears to be protected from cadmium toxicity by placental synthesis of metallothionein, but heavy exposures can overwhelm this defense

Animal studies have shown cadmium to be carcinogenic and there is a suggestion that it may increase the incidence of prostate cancer in elderly